Dengue is the leading cause of viral hemorrhagic fevers in people. Despite the fact that dengue hemorrhagic fever (DHF) has emerged to be a major problem in the Indian subcontinent, the disease and viruses circulating in the region have not received much attention. The US principal investigator of this application has recently initiated a collaborative study with Dr. Maya Gunasekera at the Genetech Research Institute in Colombo, Sri Lanka to define viral and host immune factors that increase the risk of DHF. The purpose of this FIRCA application is to request support for these collaborative studies. This research will be primarily done at the Genetech Research Institute in Sri Lanka as an extension of NIH grant RO1 AR047948 (Population Dynamics Of Borrelia Transmitted By Ticks). Although the parent grant and FIRCA application are not related scientifically, the principal investigator's group is supported by R21 (AI060865-lnteractions between dengue 3 and human dendritic cells) and F31 (AI058923-Cell Biology of dengue 3 viruses) awards to study dengue. The incidence of DHF in Sri Lanka abruptly increased several hundred fold in 1989 and the incidence has remained elevated to this date. Our previous work indicated that DHF emerged most likely because of changes in circulating virus strains. Here we propose a collaborative study to uncover viral and host immune factors responsible for severe disease. The specific aims of the application are to study 1) the relationships between dengue serotypes and genotypes currently circulating in Sri Lanka and the clinical presentation of infections, and 2) the role of pre-existing dengue immunity as a risk factor for DHF in Sri Lanka. The proposed collaboration will be beneficial to both US and Sri Lankan partners and reveal novel information about dengue epidemiology and pathogenesis. The study will also provide training opportunities for students and enhance scientific capacity in Sri Lanka. [unreadable] [unreadable] [unreadable]